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ObjectiveTo describe the respiratory trajectories and their correlation with motor function in an international pediatric cohort of patients with type 2 and nonambulant type 3 spinal muscular atrophy (SMA).MethodsThis was an 8-year retrospective observational study of patients in the International SMA Consortium (iSMAc) natural history study. We retrieved anthropometrics, forced vital capacity (FVC) absolute, FVC percent predicted (FVC%P), and noninvasive ventilation (NIV) requirement. Hammersmith Functional Motor Scale (HFMS) and revised Performance of Upper Limb (RULM) scores were correlated with respiratory function. We excluded patients in interventional clinical trials and on nusinersen commercial therapy.ResultsThere were 437 patients with SMA: 348 with type 2 and 89 with nonambulant type 3. Mean age at first visit was 6.9 (±4.4) and 11.1 (±4) years. In SMA type 2, FVC%P declined by 4.2%/y from 5 to 13 years, followed by a slower decline (1.0%/y). In type 3, FVC%P declined by 6.3%/y between 8 and 13 years, followed by a slower decline (0.9%/y). Thirty-nine percent with SMA type 2% and 9% with type 3 required NIV at a median age 5.0 (1.8–16.6) and 15.1 (13.8–16.3) years. Eighty-four percent with SMA type 2% and 80% with type 3 had scoliosis; 54% and 46% required surgery, which did not significantly affect respiratory decline. FVC%P positively correlated with HFMS and RULM scores in both subtypes.ConclusionsIn SMA type 2 and nonambulant type 3, lung function declines differently, with a common leveling after age 13 years. Lung and motor function correlated in both subtypes. Our data further define the milder SMA phenotypes and provide information to benchmark the long-term efficacy of new treatments for SMA.

ObjectivesTo report a novel association between pathogenic variants in the SEPSECS gene and complex movement disorder with thin corpus callosum (TCC).MethodsClinical exome sequencing was performed in an adult patient with a genetically unsolved neurodegenerative disorder. The main clinical, neuroimaging, and genetic data were described.ResultsThe c.865C > T (p.P289S) and c.1297T > C (p.Y433H) missense variants in SEPSECS (NM_016,955.3) were discovered.DiscussionThis case represents a novel form of early-onset pyramidal syndrome with optic nerve hypoplasia, which slowly evolved to extrapyramidal syndrome featuring dystonia-parkinsonism, associated with TCC, caused by SEPSECS pathogenic variants. This form enlarges the group of the so-called pyramidal-extrapyramidal syndromes, as well as complex hereditary spastic paraparesis with TCC.

Objective: We performed a clinical, functional, and pharmacologic characterization of the novel p.P1158L Nav1.4 mutation identified in a young girl presenting a severe myotonic phenotype. Methods: Wild-type hNav1.4 channel and P1158L mutant were expressed in tsA201 cells for functional and pharmacologic studies using patch-clamp. Results: The patient shows pronounced myotonia, slowness of movements, and generalized muscle hypertrophy. Because of general discomfort with mexiletine, she was given flecainide with satisfactory response. In vitro, mutant channels show a slower current decay and a rightward shift of the voltage dependence of fast inactivation. The voltage dependence of activation and slow inactivation were not altered. Mutant channels were less sensitive to mexiletine, whereas sensitivity to flecainide was not altered. The reduced inhibition of mutant channels by mexiletine was also observed using clinically relevant drug concentrations in a myotonic-like condition. Conclusions: Clinical phenotype and functional alterations of P1158L support the diagnosis of myotonia permanens. Impairment of fast inactivation is consistent with the possible role of the channel domain III S4-S5 loop in the inactivation gate docking site. The reduced sensitivity of P1158L to mexiletine may have contributed to the unsatisfactory response of the patient. The success of flecainide therapy underscores the usefulness of in vitro functional studies to help in the choice of the best drug for each individual.

Duchenne muscular dystrophy (DMD) is a lethal disease. The outcome measures used in numerous therapeutic trials include skeletal muscle biopsy. We studied the natural history of DMD from the standpoint of muscle histology with the aim of providing a reproducible tool for use in evaluating and comparing any histologic changes occurring in patients with DMD undergoing treatment and hence be able to determine how therapy modulates the histologic evolution of the disease.Three independent operators analyzed 56 muscle biopsies from 40 patients not treated with steroids, aged 1 to 10 years and 16 individuals treated with steroids, aged 7 to 10 years. We analyzed morphologic measures, normalized every measure for the average number of fibers observed for each year of age, and calculated intraclass correlation coefficients.The average proportion of connective tissue in patients not treated with steroids was 16.98% from ages 1 to 6 years and 30% from ages 7 to 10 years (p0.0001). The average proportion in patients treated with steroids was 24.90%. Muscle fiber area mirrored that of connective tissue in both groups.Having provided a reproducible tool for evaluation and comparison of histologic changes occurring in patients undergoing clinical trials, it was observed that at ages 6 to 7 years, fibrotic tissue rapidly peaks to 29.85%; this is a crucial moment when muscle tissue loses its self-regeneration ability, veering toward fibrotic degeneration. These data should be considered when deciding the most suitable time to begin therapy.

Objective: To test the effect of the single nucleotide polymorphism −66 T>G (rs28357094) in the osteopontin gene ( SPP1 ) on functional measures over 12 months in Duchenne muscular dystrophy (DMD). Methods: This study was conducted on a cohort of ambulatory patients with DMD from a network of Italian neuromuscular centers, evaluated longitudinally with the North Star Ambulatory Assessment (NSAA) and the 6-Minute Walk Test (6MWT) at study entry and after 12 months. Genotype at rs28357094 was determined after completion of the clinical evaluations. Patients were stratified in 2 groups according to a dominant model (TT homozygotes vs TG heterozygotes and GG homozygotes) and clinical data were retrospectively compared between groups. Results: Eighty patients were selected (age 4.1–19.3 years; mean 8.3 ± 2.7 SD). There were no differences in age or steroid treatment between the 2 subgroups. Paired t test showed a significant difference in both NSAA ( p = 0.013) and 6MWT ( p = 0.03) between baseline and follow-up after 12 months in patients with DMD carrying the G allele. The difference was not significant in the T subgroup. The analysis of covariance using age and baseline values as covariate and SPP1 genotype as fixed effect showed that these parameters are significantly correlated with the 12-month values. Conclusions: These data provide evidence of the role of SPP1 genotype as a disease modifier in DMD and support its relevance in the selection of homogeneous groups of patients for future clinical trials.

Objectives: Duchenne muscular dystrophy (DMD) is a degenerative muscle wasting disease caused by mutations in the dystrophin gene. Dystrophic muscle is characterized by chronic inflammation, and inflammatory mediators could be promising targets for innovative therapeutic interventions. We analyzed muscle biopsy samples of DMD-affected children to characterize interleukin (IL)-17 and Forkhead box P3 (Foxp3) expression levels and to identify possible correlations with clinical status. Methods: Expression levels of IL-17, Foxp3, tumor necrosis factor-α (TNF-α), monocyte chemoattractant protein-1 (MCP-1), IL-6, and transforming growth factor-β (TGF-β) were analyzed by real-time PCR in muscle biopsy samples from patients with DMD (n = 27) and juvenile dermatomyositis (JDM) (n = 8). Motor outcome of patients with DMD was evaluated by North Star Ambulatory Assessment score. Results: In DMD, we found higher levels of IL-17 and lower levels of Foxp3 mRNA compared with those for a typical inflammatory myopathy, JDM. Moreover, the IL-17/Foxp3 ratio was higher in DMD than in JDM biopsy samples. IL-17 mRNA levels appeared to be related to the expression levels of other proinflammatory cytokines (TNF-α and MCP-1) and significantly associated with clinical outcome of patients. Conclusions: The association of IL-17 expression with levels of other inflammatory cytokines and with the clinical course of DMD suggests a possible pathogenic role of IL-17.

Objective: The aim of the study was to assess different outcome measures in a cohort of ambulant boys with Duchenne muscular dystrophy (DMD) over 12 months in order to establish the spectrum of possible changes in relation to age and steroid treatment. Methods: The study is a longitudinal multicentric cohort study. A total of 106 ambulant patients with DMD were assessed using the 6-minute walk test (6MWT) and North Star Ambulatory Assessment (NSAA) at baseline and 12 months. Clinical data including age and steroid treatment were collected. Results: During the 12 months of the study, we observed a mean decline of 25.8 meters in the 6MWT with a SD of 74.3 meters. On NSAA, the mean decline was 2.2 points with a SD of 3.7. Not all the boys with DMD in our cohort showed a decline over the 12 months, with young boys showing some improvement in their 6MWT and NSAA scores up to the age of 7. NSAA and the 6MWT had the highest correlation ( r = 0.52, p Conclusions: This study provides longitudinal data of NSAA and 6MWT over a 12-month period. These data can be useful when designing a clinical trial.

The term hereditary inclusion-body myopathies (h-IBM) refers to several syndromes with autosomal recessive (AR) or dominant inheritance.1 Although clinical presentation may vary among different forms, they all lead to severe disability and share common findings at muscle biopsy. The most common form of AR h-IBM, originally described in Persian-Jewish (PJ) patients, is characterized by onset in the second to third decade of life with weakness and atrophy of distal lower limb muscles, progressing proximally with relative sparing of the quadriceps.1 AR h-IBM is associated with mutations in the UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase ( GNE ) gene on chromosome 9p12–13.2 A homozygous T→C mutation at nucleotide position (np) 2186 in the GNE gene, converting methionine to threonine, was found in all PJ patients, whereas patients of other ethnic origins were compound heterozygotes for other mutations.2 GNE mutations have been found in patients with AR Nonaka myopathy, another form of h-IBM.1,3⇓ GNE is a bifunctional enzyme with epimerase and kinase activities, which has a critical role in sialic acid biosynthesis.4 In this current study an Italian family with AR quadriceps-sparing h-IBM, previously shown to be linked to …